Blood, Toil, and Taxoteres: Biological Determinants of Treatment-Induced ctDNA Dynamics for Interpreting Tumor Response

Abstract

Collection and analysis of circulating tumor DNA (ctDNA) is one of the few methods of liquid biopsy that measures generalizable and tumor specific molecules, and is one of the most promising approaches in assessing the effectiveness of cancer care. Clinical assays that utilize ctDNA are commercially available for the identification of actionable mutations prior to treatment and to assess minimal residual disease after treatment. There is currently no clinical ctDNA assay specifically intended to monitor disease response during treatment, partially due to the complex challenge of understanding the biological sources of ctDNA and the underlying principles that govern its release. Although studies have shown pre- and post-treatment ctDNA levels can be prognostic, there is evidence that early, on-treatment changes in ctDNA levels are more accurate in predicting response. Yet, these results also vary widely among cohorts, cancer type, and treatment, likely due to the driving biology of tumor cell proliferation, cell death, and ctDNA clearance kinetics. To realize the full potential of ctDNA monitoring in cancer care, we may need to reorient our thinking toward the fundamental biological underpinnings of ctDNA release and dissemination from merely seeking convenient clinical correlates.

Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy

“…CHIP could also conceivably affect measured ctDNA concentrations [ 74 – 76 ]; however, we were unable to find clear evidence that CHIP contributed significantly to the longitudinal variability observed here (Supplementary Table 10). Therefore, as previously suggested [ 79 , 80 ], we speculate that the dynamic mutational complexity seen in blood samples from some patients may, in addition to technical factors, reflect authentic biological changes in multiple evolving metastatic lesions with differing functional states and variable responses to treatment. Levels of detectable ctDNA are also reportedly affected by variable first pass metabolism of cfDNA [ 81 ], by progressive tumour desmoplasia blocking the export of ctDNA [ 81 , 82 ], and by anatomic compartmentalisation such as the blood–brain barrier [ 83 ].…”

Mixed ctDNA dynamics and decreased detection rates in early-stage lung cancer patients during radiation treatment

“…However, it is possible that chemotherapy is a more effective means of inducing ctDNA shedding than RT or that early-stage patients do not consistently shed ctDNA in the same way as locally advanced patients do; ctDNA detection in patients with smaller tumors depends on much more than assay sensitivity. It has also been observed that changes in ctDNA abundance during therapy may be predictive of treatment efficacy, where temporary increases in ctDNA during treatment followed by ctDNA clearance is associated with improved patient outcomes (see our review, [39]). Additional studies should be done to clarify these questions.…”